Endometrial cancer is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Despite high survival rates, survivors of early stage endometrial cancer continue to experience a lower quality of life many years after diagnosis and treatment compared to healthy controls. Lifestyle factors are strongly implicated in the etiology of Type I endometrial cancer and obesity may account for over one-third of incident endometrial cancer in high-income societies. Although a number of modifiable risk factors are well-established, the mechanisms behind endometrial carcinogenesis remain unclear. Endometrial cancer is considered a model of hormonal carcinogenesis as use of postmenopausal estrogen unopposed by progesterone, and obesity are the best-established risk factors. Recent findings suggest that in addition to the sex steroid pathway, altered hormone levels in energy balance pathways may play a substantial role in disease pathogenesis. Important details such as the degree to which each pathway mediates the effects of major risk factors on disease and the specific biomarkers involved in these processes have not been elucidated. To this end, in this competing renewal we propose to understand the molecular basis for several established and novel (i.e. insulin index) risk factors of endometrial cancer, with a focus on the roles of the sex steroid and energy balance pathways. By evaluating the expression of sex steroid and energy balance related markers in tumor tissue (and matched adjacent non-tumor tissue) in relation to reproductive and lifestyle exposures, we will provide considerable insight into the importance of each of these pathways. Finally, because several modifiable and relatively strong environmental and lifestyle risk factors for endometrial cancer are well-established, endometrial cancer is a particularly suitable cancer in which to examine the interplay of environment, germline genetics, and somatic genetics. In our study with up to 36 years of follow-up, we expect to have 722 Type I endometrial cancer cases with tumor tissue available for analysis. A large prospective cohort study is a powerful approach to elucidate the biological mechanisms involved in endometrial cancer pathogenesis and identify the existence of distinct etiological subtypes. A major strength of this proposal is that it will enhance our current mechanistic understanding behind endometrial cancer susceptibility by providing us with data on somatic molecular changes influenced by established and novel endometrial cancer risk factors. Such findings would refine endometrial cancer risk prediction, creating a basis for identifying women at highest risk that would most benefit from tailored and cost-effective lifestyle and/or chemopreventive intervention strategies.